Cancer chemotherapy involves the use of cytotoxic drugs to destroy unwanted cells in patients. Treatment may consist of using one or more cytotoxic drugs, depending on the nature of the disease being treated. However, drug toxicity and drug resistance are significant barriers effective chemotherapy.
Toxicity from chemotherapeutic agents produces side effects ranging from mild trauma to death. Moreover, repeated exposure to chemotherapeutic drugs is itself often fatal. As chemotherapeutic drugs are carried in the blood, they are taken up by proliferating cells, including normal cells. Tissues with high growth rates such as bone marrow and epithelial tissues, including the gastrointestinal tract, are normally most susceptible to toxic side effects. Some drugs have additional toxic effects on other tissues, such as the urinary tract, myocardium, or pancreas. Chemotherapeutic agents may cause direct injury to the heart, either acutely, in the form of myocardial tissue injury or dysrhythmias, or in a delayed or chronic fashion associated with congestive heart failure.
Target cells, such as malignant or diseased cells, may be intrinsically resistant to chemotherapeutic drugs or they may acquire resistance as a result of exposure. A target cell may be genetically predisposed to resistance to particular chemotherapeutics. Alternatively, the cell may not have receptors or activating enzymes for the drug or may not be reliant on the biochemical process with which the drug interferes. Additionally, individuals may be inherently resistant to a drug due to altered disposition of the drug in organs other than the tumor. These mechanisms include, but are not limited to, rapid metabolism to inactive species, failure to metabolize to an active species of drug, and rapid clearance or sequestration. Many of these aspects are encoded genetically by normal polymorphisms in metabolic genes that act primarily, but not exclusively, in the liver and gastrointestinal tract and the kidneys.
Acquired resistance also may develop after cells have been exposed to a drug or to similar classes of drugs. One example of acquired drug resistance is the multiple drug resistance phenotype. Multiple drug resistance is a phenomenon of cross-resistance of cells to a variety of chemotherapeutic agents which are not structurally or functionally related. This phenomenon is typically mediated by p-glycoprotein, a cell membrane pump that is present normally on the surface of some epithelial cells. The protein actively removes drug from the cell, making it resistant to drugs that are substrates for the cell membrane pump.
A critical issue in cancer chemotherapy is the ability to select drugs that not only affect cancer cell phenotype in cell culture assays, but are also not subject to resistance whether in the tumor or intrinsic to the patient. The present invention addresses that issue.